Protection of protic functional groups by silylation has become a well-established tool in organic synthesis. Silyl ethers or silyl esters are derivatives of corresponding alcohols and carboxylic acids whose hydroxyl group has been silylated, and they are widely used as intermediates to pharmaceuticals, agrochemicals, and so forth.
A typical process for the silylation of hydroxyl groups employs compounds having a silicon-chlorine bond within the molecule, that is, chlorosilanes as silylating agents. See Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York, 1999, pp. 113-148, 237-241, 273-276, 428-431 and the references cited therein. By reacting a chlorosilane and a compound having a non-silanol hydroxyl group, the hydroxyl group is silylated to produce a silyl ether or a silyl ester.
However, the process using chlorosilanes has a number of drawbacks. First, the reaction is a dehydrochlorinative condensation in which a stoichiometric amount of highly toxic hydrogen chloride is produced as a by-product with the progress of silylating reaction. The reaction equilibrates at a certain stage, thus cannot be driven to completion unless the hydrogen chloride is removed. Therefore, the process using chlorosilanes requires that the silylating reaction be conducted typically in the presence of bases such as triethylamine, which makes the reaction not cost-effective. Moreover, as a consequence, this process entails a formation of a crystalline salt such as triethylamine hydrochloride, and thus needs a step of removing the salt from the reaction mixture. Finally, the hydrochloride salt of a substantial amount should be disposed as a waste, which also makes the process less viable.
Among silylating processes which do not form hydrogen chloride, hexamethyldisilazane is most commonly used as a silylating agent (see J. Am. Chem. Soc., 1963, Vol. 85, page 2497-2507). Nevertheless, this process still suffers from generation of toxic ammonia as a by-product. It is also possible to carry out silylation using commercially available various silylating agents such as N,O-bis(trimethylsilyl)-trifluoroacetamide and N,N′-bis(trimethylsilyl)urea (see Biochem. Biophys. Res. Commun., 1968, Vol. 31, page 616-622, and Synthesis, 1981, page 807-809). However, large amounts of by-products originating from the silylating agents are produced, which necessitates the step of removing the by-products and isolating the desired compound.
It is also known to use hydrosilanes as silylating agents and subject alcohols to dehydrogenation reaction therewith for silylation. This process carries out reaction in the presence of catalysts such as palladium on activated carbon, transition metal complexes, tris(pentafluorophenyl)-borane, tetrabutylammonium fluoride and the like (see Chem. Lett., 1973, page 501-504, J. Org. Chem., 1999, Vol. 64, page 4887-4892, Tetrahedron Lett., 1994, Vol. 35, page 8413-8414). The by-product is hydrogen gas, which provides the advantage that the step of separating the silylated compound and the by-product is eliminated. However, it comes with a serious disadvantage, the increase in the risk of potential explosion, especially when practiced on a large scale, because hydrogen gas has a wide range of explosion.
On the other hand, it was reported to use tert-butyldimethylsilanol as a silylating agent (see Tetrahedron Lett., 1991, page 7159-7160). In this process, an alcohol and the silanol are subjected to a formal dehydrative condensation under Mitsunobu reaction conditions, but an expensive reagent must be used and large amounts of by-products are formed therefrom.
To solve the aforementioned problems, there is a need to have a method for preparing silyl ethers or silyl esters without forming a substantial amount of harmful by-products such as hydrogen chloride or triethylamine hydrochloride.